The present invention relates to processes for preparing substituted 1,3-oxathiolanes with antiviral activity and intermediates of use in their preparation.
Nucleosides, and in particular, 1,3-oxathiolanes and their analogues and derivatives are an important class of therapeutic agents. For example, a number of nucleosides have shown antiviral activity against retroviruses such as human immunodeficiency viruses (HIV), hepatitis B virus (HBV) and human T-lymphotropic virus (HTLV).
The most potent anti-HIV compounds thus far reported are 2xe2x80x2,3xe2x80x2-dideoxynucleosides, more particularly, 2xe2x80x2,3xe2x80x2-dideoxycytidine (ddC) and 3xe2x80x2-azido-2xe2x80x2,3xe2x80x2-dideoxythymidine (AZT). These compounds are also active against other kinds of retroviruses such as the Moloney murine leukemia virus. However, clinically, both compounds are toxic.
A structurally distinct class of compounds known as 2-substituted-5-substituted-1,3-oxathiolanes has been found to have superior antiviral and antiretroviral activity without cell toxicity. See, e.g., EP 0382526A and WO 91/17159 the disclosures of which are incorporated herein by reference.
Because of the increasing incidence and the life-threatening characteristics of AIDS, there is a great need to develop a general synthetic scheme for substituted 1,3-oxathiolanes which is efficient, amenable to large scale, inexpensive and based on readily available starting material. It is therefore an advantage of the present invention to provide synthesis of substituted 1,3-oxathiolanes that is readily feasible.
The processes of this invention may be used to prepare the compounds of formula (I) and pharmaceutically acceptable salts or esters thereof: 
wherein R2 is a purine or pyrimidine base or an analogue or derivative thereof; and Z is S, Sxe2x95x90O or SO2.
It will be appreciated by those skilled in the art that the compounds of formula (I) contain at least two chiral centers (shown as * in formula (I)) and thus exist in the form of two pairs of optical isomers (i.e., enantiomers) and mixtures thereof including racemic mixtures. Thus the compounds of formula (I) may be either cis isomers, as represented by formula (II), or trans isomers, as represented by formula (III), or mixtures thereof. Each of the cis and trans isomers can exist as one of two enantiomers or as mixtures thereof including racemic mixtures. The preparation of all such isomers and mixtures thereof including racemic mixtures is included within the scope of the invention. 
It will also be appreciated that when Z is Sxe2x95x90O the compounds exist in two additional isomeric forms as shown in formulas (IIa) and (IIb) which differ in the configuration of the oxide oxygen atom relative to the 2,5-substituents. The processes of this invention additionally embrace the preparation of such isomers and mixtures thereof. 
The purine or pyrimidine base or analogue or derivative thereof R2 will be linked at any position of the base, preferably at the N9- or N1-position, respectively.
By xe2x80x9cpurine or pyrimidine basexe2x80x9d or an analogue or derivative thereof is meant a purine or pyrimidine base found in native nucleosides or an analogue, thereof which mimics such bases in that their structures (the kinds of atoms and their arrangement) are similar to the native bases but may either possess additional or lack certain of the functional properties of the native bases. Such analogues include those derived by replacement of a CH2 moiety by a nitrogen atom (for example, 5-azapyrimidines such as 5-azacytosine) or vice verse (for example 7-deazapurines, for example 7-deazadenosine or 7-deazaguanosine) or both (e.g., 7-deaza-8-azapurines). By derivatives of such bases or analogues are meant those compounds wherein ring substituents are either incorporated, removed or modified by conventional substituents known in the art, e.g., halogen, hydroxyl, amino, C1-6 alkyl. Such purine or pyrimidine bases, analogues and derivatives will be well known to those skilled in the art.
Preferably the group R2 is selected from: 
wherein:
X is oxygen or sulfur; Y is oxygen or sulfur;
R3 and R4 are independently selected from the group consisting of hydrogen, hydroxyl, amino, substituted or unsubstituted C1-6 alkyl, or C1-6 alkenyl or C1-6 alkynyl, and substituted or unsubstituted C1-10 acyl or aracyl;
R5 and R6 are independently selected from the group consisting of hydrogen, halogen, hydroxyl, amino, cyano, carboxy, carbamoyl, alkoxycarbonyl, hydroxymethyl, trifluoromethyl, thioaryl, substituted or unsubstituted C1-6 alkyl or C1-6 alkenyl or C1-6 alkynyl, and substituted or unsubstituted C1-10 acyloxy;
and 
wherein:
R7 and R8 are independently selected from the group consisting of hydrogen, hydroxy, alkoxy, thiol, thioalkyl, amino, substituted amino, halogen, cyano, carboxy, alkoxycarbonyl, carbamoyl, substituted or unsubstituted C1-6 alkyl, or alkenyl, or alkynyl, and substituted or unsubstituted C1-10 acyloxy; and
R9 and R10 are independently selected from the group consisting of hydrogen, hydroxyl, alkoxy, amino, substituted amino, halogen, azido, substituted or unsubstituted C1-6 alkyl or alkenyl or alkynyl, and substituted or unsubstituted C1-10 acyloxy.
More preferably, the R2 group is selected from: 
wherein each R11 is independently selected from hydrogen, acetyl, and C1-6 alkyl groups;
R12 and R13 are independently selected from hydrogen, hydroxymethyl, trifluoromethyl, substituted or unsubstituted C1-6 alkyl or alkenyl, bromine, chlorine, fluorine, and iodine;
R14 is selected from hydrogen, cyano, carboxy, ethoxycarbonyl, carbamoyl, and thiocarbamoyl; and each W is independently selected from hydrogen, bromine, chlorine, fluorine, iodine, amino, and hydroxyl groups.
Most preferably R2 is 
wherein R3 and R6 are hydrogen, and R4 and R5 are as defined above.
Z is preferably xe2x80x94Sxe2x80x94.
By xe2x80x9ca pharmaceutically acceptable salt or esterxe2x80x9d is meant any pharmaceutically acceptable salt, ester, or salt of such ester, of a compound of formula (I) or any other compound which, upon administration to the recipient, is capable of providing (directly or indirectly) a compound of formula (I) or an antivirally active metabolite or residue thereof.
It will be appreciated by those skilled in the art that the compounds of formula (I) may be modified to provide pharmaceutically acceptable derivatives thereof, at functional groups in both the base moiety, R2, and at the hydroxymethyl group of the oxathiolane ring. Modification at all such functional groups is included within the scope of the processes of this invention. However, of particular interest are pharmaceutically acceptable derivatives (e.g., esters) obtained by modification of the 2-hydroxymethyl group of the oxathiolane ring.
Preferred esters of the compounds of formula (I) produced by the process of this invention include the compounds in which OH is replaced by a carboxyl function R(CO)Oxe2x80x94 in which the non-carbonyl moiety R is selected from hydrogen, straight or branched chain alkyl (e.g. methyl, ethyl, n-propyl, t-butyl, n-butyl), alkoxyalkyl (e.g. methoxymethyl), aralkyl (e.g. benzyl), aryloxyalkyl (e.g. phenoxymethyl), aryl (e.g. phenyl optionally substituted by halogen, C1-4 alkyl or C1-4 alkoxy), substituted dihydropyridinyl (e.g. N-methyldihydropyridinyl). The OH function may also be replaced by sulphonate esters such as alkyl or aralkylsulphonyl (e.g. methanesulphonyl); sulfate esters, amino acid esters (e.g. L-valyl or L-isoleucyl), or mono-, di- or tri-phosphate esters. Also included within the scope of such esters are esters derived from polyfunctional acids such as carboxylic acids containing more than one carboxyl group, for example, dicarboxylic acids HOOC(CH2)qCOOH where q is an integer of 0 to 10 (for example, succinic acid) or phosphoric acids.
Methods for preparing such esters are well known. See, for example, Hahn et al., xe2x80x9cNucleotide Dimers as anti-Human Immunodeficiency Virus Agentsxe2x80x9d, Nucleotide Analogues, pp. 156-159 (1989) and Busso et al., xe2x80x9cNucleotide Dimers Supress HIV Expression In Vitroxe2x80x9d, AIDS Research and Human Retroviruses, 4(6), pp.449-455 (1988). Where esters are derived from such acids, each acidic group is preferably esterified by a compound of formula (I) or other nucleoside or analogs and derivatives thereof to provide esters of the formula: 
where W is xe2x80x94OCxe2x80x94(CH2)nxe2x80x94COxe2x80x94 where n is an integer of 0 to 10, a phosphate group, or a thiophosphate group, Z and R2 are as defined above, and
J is any nucleoside or nucleoside analog or derivative thereof.
Among the preferred nucleosides and nucleoside analogs are 3xe2x80x2-azido-2xe2x80x2,3xe2x80x2-dideoxythymidine; 2xe2x80x2,3xe2x80x2-dideoxycytidine; 2xe2x80x2,3xe2x80x2-dideoxyadenosine; 2xe2x80x2,3xe2x80x2-dideoxyinosine; 2xe2x80x2,3xe2x80x2-dideoxythymidine; 2xe2x80x2,3xe2x80x2-dideoxy-2xe2x80x2,3xe2x80x2-didehydrothymidine; 2xe2x80x2,3xe2x80x2-dideoxy-2xe2x80x2,3xe2x80x2-didehydrocytidine and ribavirin and those nucleosides whose bases are depicted on pages 4-5 of this specification. The most preferred nucleoside or nucleoside analog is chosen among the compounds of formula (I) to form a homodimer consisting of two nucleosides of formula (I).
With regard to the above described esters, unless otherwise specified, any alkyl moiety present advantageously contains 1 to 16 carbon atoms, preferably 1 to 4 carbon atoms and could contain one or more double bonds. Any aryl moiety present in such esters advantageously comprises a phenyl group.
In particular, the esters may be a C1-16 alkyl ester, an unsubstituted benzoyl ester or a benzoyl esters substituted by at least one halogen (bromine, chlorine, fluorine or iodine), C1-6 alkyl or alkenyl, saturated or unsaturated C1-6 alkoxy, nitro or trifluoromethyl groups.
Pharmaceutically acceptable salts of the compounds of formula (I) include those derived from pharmaceutically acceptable inorganic and organic acids and bases. Examples of suitable acids include hydrochloric, hydrobromic, sulfuric, nitric, perchloric, fumaric, maleic, phosphoric, glycollic, lactic, salicylic, succinic, p-toluenesulfonic, tartaric, acetic, citric, methanesulfonic, formic, benzoic, malonic, naphthalene-2-sulfonic, and benzenesulfonic acids. Other acids such as oxalic, while not in themselves pharmaceutically acceptable, may be useful in the preparation of salts useful as intermediates in obtaining the compounds of the invention and their pharmaceutically acceptable acid addition salts.
Salts derived from appropriate bases include alkali metal (e.g. sodium), alkaline earth metal (e.g. magnesium), ammonium and N(Rxe2x80x2)4+ (where Rxe2x80x2 is C1-4 alkyl) salts.
In the processes for preparing the compounds of this invention, the following definitions are used:
R1 is a hydroxyl protecting function such as an acyl having from 1 to 16 carbon atoms unsubstituted or substituted with a heteroatom (e.g. benzoyl), or a silyl function such as trialkylsilyl (e.g. t-butyldimethylsilyl);
R2 is a purine or pyrimidine base or an analogue or derivative thereof;
Rw is hydrogen or R1;
Rx is a substituted or unsubstituted C1-6 alkyl;
Ry is a substituted or unsubstituted C1-12 alkyl or substituted or unsubstituted C6-20 aryl; and
L is a leaving group.
As used in the processes of this invention, a xe2x80x9cleaving groupxe2x80x9d is an atom or group which is displaceable upon reaction with an appropriate base, with or without a Lewis acid. Suitable leaving groups include alkoxy carbonyl groups such as ethoxy carbonyl; halogens such as iodine, bromine or chlorine, fluorine; substituted or unsubstituted saturated or unsaturated thiolates, such as thiomethyl or thiophenyl; substituted or unsubstituted saturated or unsaturated selenino compounds, such as phenyl selenide or alkyl selenide; substituted or unsubstituted saturated or unsaturated aliphatic or aromatic ketones such as methyl ketone; or xe2x80x94ORz where Rz is hydrogen or a substituted or unsubstituted saturated or unsaturated alkyl group, e.g., a C1-6 alkyl or alkenyl group such as methyl; a substituted or unsubstituted aliphatic or aromatic acyl group, e.g., a C1-6 aliphatic acyl group such as acetyl and an aromatic acyl group such as benzoyl; a substituted or unsubstituted saturated or unsaturated alkoxy carbonyl group, such as methyl carbonate and phenyl carbonate; substituted or unsubstituted sulphonyl imidazolide; substituted or unsubstituted carbonyl imidazolide; substituted or unsubstituted aliphatic or aromatic amino carbonyl group, such as phenyl carbamate; substituted or unsubstituted alkyl imidate group such as trichloroacetamidate; substituted or unsubstituted saturated or unsaturated phosphinoyl, such as diethylphosphinoyl; substituted or unsubstituted aliphatic or aromatic sulphonyl group, such as tosylate.
One process according to the invention is illustrated in SCHEME 1. The process of SCHEME 1 is further illustrated using specific reagents and compounds in SCHEMES 1A and 1B.
The various steps involved in the synthesis as illustrated in SCHEME 1 may be briefly described as follows:
Step 1: A mercaptoacetaldehyde monomer produced from the dimer in a suitable solvent is reacted directly with any aldehyde of the formula RwOCH2CHO (VII) to yield an oxathiolane lactol of formula (XIII).
The glycoaldehyde derivative of formula (VII) may be generated from the dimer by any means known in the art as depicted in SCHEME 1B.
Step 2: The hydroxyl group of the compound of formula (XIII) is converted to a leaving group with a suitable reagent in a compatible organic solvent to yield an important oxathiolane intermediate of formula (XIV).
Step 3: The oxathiolane intermediate of formula (XIV) is reacted with a previously silylated purine or pyrimidine base to give a purin-9xe2x80x2-yl or pyrimidin-1xe2x80x2-yl substituted oxathiolane of formula (IX) where Z is sulfur.
Optionally, the sulfur may be oxidized at this stage or at any other following stage to obtain compounds where Z is Sxe2x95x90O or SO2.
Step 4: The base R2 shown in formula (IX) is acylated in a suitable solvent to yield a compound of formula (X) where R2xe2x80x2 is acylated-R2 which provides for easier separation of isomers.
Therefore, at this stage, the compound of formula (X) is optionally separated to its cis or trans isomer.
Step 5: The acyl functionalities of R2xe2x80x2 and R1COOCH2 of compound of formula (X) are hydrolyzed under basic conditions (sequentially or at the same time) to yield an oxathiolane of formula (I). 
SCHEME 1A:
Step 1: A mercaptoacetaldehyde monomer produced from the dimer in pyridine is reacted directly with benzoyloxyacetaldehyde (VII-A) to yield an oxathiolane lactol of formula (XIII-A).
Step 2: The hydroxyl group of the compound of formula (XIII-A) is converted to a leaving group with acetyl chloride in a compatible organic solvent; such as dichloromethane or chloroform, to yield intermediate of formula (XIV-A).
Step 3: The oxathiolane intermediate of formula (XIV-A) is reacted with a previously silylated cytosine to give a cytosin-1xe2x80x2-yl oxathiolane of formula (IX-A).
Step 4: The amine function of the base in compound of formula (IX-A) is acylated with acetic anhydride in pyridine to yield a compound of formula (X-A) which provides for easier separation of isomers.
Step 5: The acyl functions of the compound of formula (X-A) are hydrolyzed with ammonia in methanol to yield an oxathiolane of formula (I-A). 
SCHEME 1B:
The glycoaldehyde dimer (VII-B) is used as a source of the glycoaldehyde. 
A second and preferred process for producing oxathiolane compounds is illustrated in SCHEME 2. This process is further illustrated using specific reagents and compounds in SCHEME 2A.
The various steps involved in the synthesis as illustrated in SCHEME 2 may be briefly described as follows:
Step 1: Mercaptoacetaldehyde monomer produced from the dimer in a suitable solvent is reacted directly with any organic glyoxylate of the formula RyOOCCHO to yield an oxathiolane lactol of formula (XV).
Step 2: The hydroxyl group of the compound of formula (XV) is converted to a leaving group with a suitable reagent in a compatible organic solvent to yield an important oxathiolane intermediate of formula (XVI).
Step 3: The oxathiolane intermediate of formula (XVI) is reacted with a previously silylated purine or pyrimidine base, in the presence of a Lewis acid, to give purin-9xe2x80x2-yl or pyrimidin-1xe2x80x2-yl substituted oxathiolane of formula (XVII) where Z is S, predominantly as the cis-isomer.
Optionally, the sulfur may be oxidized at this stage or at any other following stage to give compounds where Z is Sxe2x95x90O or SO2.
Step 4: The ester group of the oxathiolane of formula (XVII) is selectively reduced with a suitable reducing agent in a compatible organic solvent to yield an oxathiolane nucleoside of formula (XVIII).
At this stage, the compound of formula (XVIII) is optionally separated to its cis and trans isomers.
Step 5: The hydroxyl group of the compound of formula (XVIII) is protected with a suitable silyl protecting group in an appropriate solvent to yield an oxathiolane of formula (XIX).
Step 6: The R2 base of formula (XIX-A) can be interconverted to another base R2a by reaction with a suitable reagent to yield an oxathiolane of formula (XX).
Step 7: The protecting group R1 of the compound of formula (XX) is removed under neutral conditions using a suitable reagent in a suitable solvent to yield the oxathiolane of formula (I). 
SCHEME 2A:
Step 1: Mercaptoacetaldehyde dimer in pyridine is reacted directly with ethyl glyoxylate to yield an oxathiolane lactol of formula (XV-A).
Step 2: The hydroxyl group of the compound of formula (XV-A) is converted to an acetyl leaving group with acetyl chloride in a compatible organic solvent such as dichloromethane, chloroform or pyridine, to yield intermediate of formula (XVI-A).
Step 3: The oxathiolane intermediate of formula (XVI-A) is reacted with previously silylated uracil, in the presence of trimethylsilyl iodide, to give uracil-1xe2x80x2-yl oxathiolane of formula (XVII-A), predominantly as the cis-isomer.
Step 4: The ester group of the oxathiolane of formula (XVII-A) is selectively reduced with sodium borohydride in methanol to yield an oxathiolane nucleoside of formula (XVIII-A).
Step 5: The hydroxyl group of the compound of formula (XVIII-A) is protected with t-butyldimethyl silyl in dimethylformamide (DMF) to yield an oxathiolane of formula (XIX-A).
Step 6: The uracil base of formula (XIX-A) can be interconverted to cytosine, by reaction with p-chlorophenoxy phosphorous oxychloride followed by amination with ammonia in methanol to yield an oxathiolane of formula (XX-A).
Step 7: The silyl group of the compound of formula (XX-A) is removed under neutral conditions using tetra n-butyl ammonium fluoride in tetrahydrofuran to yield the oxathiolane of formula (I). 
Although the process of Scheme 2 generally provides nucleoside analogues predominantly in their cis form, such a process is most preferred for pyrimidine bases because of high cis-selectivity.
For purines, although the process of Scheme 2 does yield more cis isomer than trans, the ratio obtained is moderate. An alternative process has been designed to obtain purin-yl nucleosides in high cis: trans ratios.
Briefly, steps 1 and 2 of Scheme 2 remain the same. However, the coupling procedure (step 3) between the compound of formula (XVI) and the base (preferably purine) is modified as follows:
Step 3a: The oxathiolane intermediate of formula (XVI) is reacted with a halogen-containing silyl Lewis acid such as trimethylsilyl iodide, to give an intermediate of formula (XXVI): 
Step 3b: The intermediate of formula (XXVI) is then mixed with a base (preferably a purine) under basic conditions to yield the intermediate of formula (XVII) predominantly as the cis isomer.
As an alternative to process 2, a third process according to this invention for producing oxathiolane compounds is illustrated in SCHEME 3. This process is illustrated using specific reagents and compounds, for example, in SCHEME 3A.
The various steps involved in the synthesis as illustrated in SCHEME 3 may be briefly described as follows:
Step 1: Similar to SCHEME 2.
Step 2: The hydroxyl group of the intermediate of formula (XV), is converted to a leaving group with a suitable reagent in a compatible organic solvent to yield an important intermediate of formula (XXI).
Step 3: The ester group of the intermediate of formula (XXI) is selectively reduced with a suitable reducing agent in a compatible organic solvent and the resultant hydroxyl group is directly protected with a suitable group R1 to yield an oxathiolane of formula (XXII).
Step 4: The oxathiolane of formula (XXII) is reacted with previously silylated purine or pyrimidine base in the presence of a Lewis Acid to give a pyrimidin-1xe2x80x2-yl or purin-9xe2x80x2-yl oxathiolane of formula (XXIII) where Z is S (optionally oxidized to Sxe2x95x90O or SO2).
Step 5: The base R2 shown in formula (XXIII) is acylated with acetic anhydride in a solvent to yield a compound of formula (XXIV) where R2xe2x80x2 is an acylated R2 which provides for easier separation of isomers.
Therefore, at this stage, the compound of formula (X) is optionally separated to its cis or trans isomer.
Step 6: The acetyl functionality of R2xe2x80x2 of the compound of formula (XXIV) is hydrolyzed under basic conditions to yield an oxathiolane of formula (XXV).
Step 7: Removal of the R1 protecting group is effected by suitable reagents in a compatible solvent to yield an oxathiolane of formula (I). 
SCHEME 3A:
Step 2: The hydroxyl group of the intermediate of formula (XV-A), is converted to a carbonate leaving group with methyl chloroformate in a compatible organic solvent to yield an intermediate of formula (XXI-A)
Step 3: The ester group of the intermediate of formula (XXI-A) is selectively reduced with sodiumborohydride in methanol and the resultant hydroxyl group is directly protected with t-butyldiphenylsilyl to yield an oxathiolane of formula (XXII-A).
Step 4: The oxathiolane of formula (XXII-A) is reacted with previously silylated cytosine, in the presence of trimethylsilyltriflate or iodotrimethylsilane, to give cytosin-1xe2x80x2-yl oxathiolane of formula (XXIII-A).
Step 5: The amine function of the cytosine of compound (XXIII-A) is acylated with acetic anhydride in pyridine to yield a compound of formula (XXIV-A) so that the cis- and trans-isomers may be separated.
Step 6: The acetyl functionality of the compound of formula (XXIV-A) is hydrolyzed under basic conditions to yield an oxathiolane of formula (XXV-A).
Step 7: Removal of the silyl group is effected by using tetra-n-butylammonium fluoride in tetrahydrofuran yield an oxathiolane of formula (I). 
In the processes of this invention, the following intermediates are of particular importance:
trans-2-hydroxymethyl-5-acetoxy-1,3-oxathiolane;
cis-2-benzoyloxymethyl-5-hydroxy-1,3-oxathiolane, trans-2-benzoyloxymethyl-5-hydroxy-1,3-oxathiolane and mixtures thereof;
cis-2-benzoyloxymethyl-5-(4xe2x80x2,5xe2x80x2-dichlorobenzoyloxy)-1,3-oxathiolane, trans-2-benzoyloxymethyl-5-(4xe2x80x2,5xe2x80x2-dichlorobenzoyloxy)-1,3-oxathiolane and mixtures thereof;
cis-2-benzoyloxymethyl-5-trimethylacetoxy-1,3-oxathiolane, trans-2-benzoyloxymethyl-5-trimethylacetoxy-1,3-oxathiolane and mixtures thereof;
cis-2-benzoyloxymethyl-5-(2xe2x80x2,2xe2x80x2,2xe2x80x2-trichloroethoxycarbonyloxy)1,3-oxathiolane, trans-2-benzoyloxymethyl-5-(2xe2x80x2,2xe2x80x2,2xe2x80x2-trichloroethoxy carbonyloxy)1,3-oxathiolane and mixtures thereof;
cis-2-benzoyloxymethyl-5-ethoxycarbonyloxy-1,3-oxathiolane, trans-2-benzoyloxymethyl-5-ethoxycarbonyloxy-1,3-oxathiolane and mixtures thereof;
cis-2-benzoyloxymethyl-5-methoxycarbonyloxy-1,3-oxathiolane, trans-2-benzoyloxymethyl-5-methoxycarbonyloxy-1,3-oxathiolane and mixtures thereof;
cis-2-benzoyloxymethyl-5-acetoxy-1,3-oxathiolane, trans-2-benzoyloxymethyl-5-acetoxy-1,3-oxathiolane and mixtures thereof;
cis-2-benzoyloxymethyl-5-(N4xe2x80x2-acetylcytosin-1xe2x80x2-yl)-1,3-oxathiolane, trans-2-benzoyloxymethyl-5-(N4xe2x80x2-acetylcytosin-1xe2x80x2-yl)-1,3-oxathiolane and mixtures thereof;
cis-2-benzoyloxymethyl-5-(cytosin-1xe2x80x2-yl)-1,3-oxathiolane, trans-2-benzoyloxymethyl-5-(cytosin-1xe2x80x2-yl)-1,3-oxathiolane and mixtures thereof;
cis-2-carboethoxy-5-hydroxy-1,3-oxathiolane, trans-2-carboethoxy-5-hydroxy-1,3-oxathiolane and mixtures thereof;
cis-2-carboethoxy-5-methoxycarbonyloxy-1,3-oxathiolane, trans-2-carboethoxy-5-methoxycarbonyloxy-1,3-oxathiolane and mixtures thereof;
cis-2-carboethoxy-5-acetoxy-1,3-oxathiolane, trans-2-carboethoxy-5-acetoxy-1,3-oxathiolane and mixtures thereof;
cis-2-carboethoxy-5-(N4xe2x80x2-acetylcytosin-1xe2x80x2-yl)-1,3-oxathiolane;
cis-2-carboethoxy-5-(cytosin-1xe2x80x2-yl)-1,3-oxathiolane;
cis-2-carboethoxy-5-(uracil-1xe2x80x2-yl)-1,3-oxathiolane;
cis-2-benzoyloxymethyl-5-(cytosin-1xe2x80x2-yl)-1,3-oxathiolane;
cis-ethyl-5-iodo-1,3-oxathiolan-2-carboxylate, trans-ethyl-5-iodo-1,3-oxathiolan-2-carboxylate and mixtures thereof;
cis-ethyl-5-(6xe2x80x2-chloropurin-9xe2x80x2-yl)-1,3-oxathiolan-2-carboxylate, trans-ethyl-5-(6xe2x80x2-chloropurin-9xe2x80x2-yl)-1,3-oxathiolan-2-carboxylate and mixtures thereof; and
cis-ethyl-5-(6xe2x80x2-chloropurin-7xe2x80x2-yl)-1,3-oxathiolan-2-carboxylate, trans-ethyl-5-(6xe2x80x2-chloropurin-7xe2x80x2-yl)-1,3-oxathiolan-2-carboxylate and mixtures thereof.
Some of the steps described hereinabove have been reported in the context of purine nucleoside synthesis, for example, in xe2x80x9cNucleoside Analoguesxe2x80x94Chemistry, Biology and Medical Applicationsxe2x80x9d, R. T. Walker et al., Eds, Plenum Press, New York (1979) at pages 193-223, the text of which is incorporated herein by reference.
It will be appreciated that the reactions of the above described processes may require the use of, or conveniently may be applied to, starting materials having protected functional groups, and deprotection might thus be required as an intermediate or final step to yield the desired compound. Protection and deprotection of functional groups may be effected using conventional means. Thus, for example, amino groups may be protected by a group selected from aralkyl (e.g., benzyl), acyl or aryl (e.g., 2,4-dinitrophenyl); subsequent removal of the protecting group being effected when desired by hydrolysis or hydrogenolysis as appropriate using standard conditions. Hydroxyl groups may be protected using any conventional hydroxyl protecting group, for example, as described in xe2x80x9cProtective Groups in Organic Chemistryxe2x80x9d, Ed. J. F. W. McOmie (Plenum Press, 1973) or xe2x80x9cProtective Groups in Organic Synthesisxe2x80x9d by Theodora W. Greene (John Wiley and Sons, 1991). Examples of suitable hydroxyl protecting groups include groups selected from aralkyl (e.g., benzyl, diphenylmethyl or triphenylmethyl), heterocyclic groups such as tetrahydropyranyl, acyl, (e.g., acetyl or benzoyl) and silyl groups such as trialkylsilyl (e.g., t-butyldimethylsilyl). The hydroxyl protecting groups may be removed by conventional techniques. Thus, for example, alkyl, silyl, acyl and heterocyclic groups may be removed by solvolysis, e.g., by hydrolysis under acidic or basic conditions. Aralkyl groups such as triphenylmethyl may similarly be removed by solvolysis, e.g., by hydrolysis under acidic conditions. Aralkyl groups such as benzyl may be cleaved, for example, by hydrogenolysis. Silyl groups may also conveniently be removed using a source of fluoride ions such as tetra-n-butylammonium fluoride.
In the above processes the compounds of formula (I) are generally obtained as a mixture of the cis and trans isomers. However, in the process depicted in Scheme 2, the ratio of cis:trans may approach 15:1 for pyrimidines, whereas it may approach 10:1 for the purines in the case of the modified process of Scheme 2.
These isomers may be separated, for example, by acetylation, e.g., with acetic anhydride followed by separation by physical means, e.g., chromatography on silica gel and deacetylation, e.g., with methanolic ammonia or by fractional crystallization.
Pharmaceutically acceptable salts of the compounds of the invention may be prepared as described in U.S. Pat. No. 4,383,114, the disclosure of which is incorporated by reference herein. Thus, for example, when it is desired to prepare an acid addition salt of a compound of formula (I), the product of any of the above procedures may be converted into a salt by treatment of the resulting free base with a suitable acid using conventional methods.
Pharmaceutically acceptable acid addition salts may be prepared by reacting the free base with an appropriate acid optionally in the presence of a suitable solvent such as an ester (e.g., ethyl acetate) or an alcohol (e.g., methanol, ethanol or isopropanol). Inorganic basic salts may be prepared by reacting the free base with a suitable base such as an alkoxide (e.g., sodium methoxide) optionally in the presence of a solvent such as an alcohol (e.g., methanol). Pharmaceutically acceptable salts may also be prepared from other salts, including other pharmaceutically acceptable salts, of the compounds of formula (I) using conventional methods.
A compound of formula (I) may be converted into a pharmaceutically acceptable phosphate or other ester by reaction with a phosphorylating agent, such as POCl3, or a suitable esterifying agent, such as an acid halide or anhydride, as appropriate. An ester or salt of a compound of formula (I) may be converted to the parent compound, for example, by hydrolysis.
Where the compound of formula (I) is desired as a single isomer it may be obtained either by resolution of the final product or by stereospecific synthesis from isomerically pure starting material or any convenient intermediate.
Resolution of the final product, or an intermediate or starting material therefore may be effected by any suitable method known in the art: see for example, Stereochemistry of Carbon Compounds, by E. L. Eliel (McGraw Hill, 1962) and Tables of Resolving Agents, by S. H. Wilen.
The invention will be further described by the following examples which are not intended to limit the invention in any way. All temperatures are in degrees celsius.
Examples 1 to 7, and 19 to 23 relate to the process as depicted in Scheme 1. Examples 8 to 10, and 13 to 18 relate to the process as depicted in Scheme 2, and Examples 11, 12, and 19 to 21 relate to the process as depicted in Scheme 3. Examples 24 and 25 relate to the modified process as depicted in Scheme 2 (preferably for purines) and summarized on page 20 of this application.